There is evidence that under certain circumstances brain uses fuels other than glucose to a considerable extent and that the permeability of the blood-brain barrier to blood-borne fuels decreases during the course of development. Use of non-glucose fuels is of particular importance when brain glucose utilization is inhibited, as occurs during respiratory acidosis. We will develop methods for measuring rates of utilization by brain of blood ketone bodies and lactate, based on the uptake of 14C-labelled beta-hydroxybutyrate and lactate from blood. These methods will be used to study interactions between these fuels and glucose during development and during inhibition of brain glucose utilization by hypercapnia. A method to measure the rate of oxygen consumption by brain by following the rate of disappearance of 14C from labelled Krebs cycle intermediates and amino acids will also be developed in order to evaluate energy metabolism of brain when rates of utilization of non-glucose substrates are high and during hypoxia. The hypothesis that the protective effect of hypercapnia against hypoxia is by increasing O2 delivery to brain will be examined and alternate hypotheses tested. The inhibition of brain glucose utilization by hypercapnic acidosis will be measured at a number of different initial rates of glucose utilization to test the hypothesis that the degree of inhibition for a given CO2 level is a constant fraction of the initial rate, thus allowing the initial rate to be calculated from the rate of decrease in concentrations of intermediary metabolites and amino acids. Further work on the isolation of specific proteins which supply amino acids for oxidation during hypercapnia is planned if current efforts to show that increased proteolysis occurs are successful.